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Identification of Compounds with pH-Dependent Bactericidal Activity against Mycobacterium tuberculosis.

Authors
  • Early, Julie1
  • Ollinger, Juliane1
  • Darby, Crystal2
  • Alling, Torey1
  • Mullen, Steven1
  • Casey, Allen1
  • Gold, Ben2
  • Ochoada, Jason3
  • Wiernicki, Todd3
  • Masquelin, Thierry3
  • Nathan, Carl2
  • Hipskind, Philip A3
  • Parish, Tanya1
  • 1 TB Discovery Research , Infectious Disease Research Institute , 1616 Eastlake Avenue E , Suite 400, Seattle , Washington 98102 , United States. , (United States)
  • 2 Department of Microbiology and Immunology , Weill Cornell Medical College , 1300 York Avenue , Box 62, New York , New York 10065 , United States. , (United States)
  • 3 Lilly Research Laboratories , Eli Lilly and Company , 307 E Merrill Street , Indianapolis , Indiana 46285 , United States. , (India)
Type
Published Article
Journal
ACS Infectious Diseases
Publisher
American Chemical Society
Publication Date
Feb 08, 2019
Volume
5
Issue
2
Pages
272–280
Identifiers
DOI: 10.1021/acsinfecdis.8b00256
PMID: 30501173
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

To find new inhibitors of Mycobacterium tuberculosis that have novel mechanisms of action, we miniaturized a high throughput screen to identify compounds that disrupt pH homeostasis. We adapted and validated a 384-well format assay to determine intrabacterial pH using a ratiometric green fluorescent protein. We screened 89000 small molecules under nonreplicating conditions and confirmed 556 hits that reduced intrabacterial pH (below pH 6.5). We selected five compounds that disrupt intrabacterial pH homeostasis and also showed some activity against nonreplicating bacteria in a 4-stress model, but with no (or greatly reduced) activity against replicating bacteria. The compounds selected were two benzamide sulfonamides, a benzothiadiazole, a bissulfone, and a thiadiazole, none of which are known antibacterial agents. All of these five compounds demonstrated bactericidal activity against nonreplicating bacteria in buffer. Four of the five compounds demonstrated increased activity under low pH conditions. None of the five compounds acted as ionophores or as general disrupters of membrane potential. These compounds are useful starting points for work to elucidate their mechanism of action and their utility for drug discovery.

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